The studies proposed focus on delineating the immunoregulatory mechanisms of allograft rejection, especially the contribution of MHC antigen expression by the parenchymal cells of islet allografts to immunity. We have observed that class II expression by islet endocrine cells may not only be incapable of inducing an alloimmune response but also that class II antigen presented by such cells can induce a state of functional paralysis in the responding T cells. We will examine whether tolerance induction in vivo is attributable to a process of clonal deletion of T cell anergy. We will also determine whether T cell paralysis is associated with acquisition of suppressor activity. We will attempt to utilize this novel mechanism of T cell tolerance induction to promote the survival of otherwise highly immunogenic islet grafts. Unlike expression of class II antigen by islet endocrine cells, the level class I MHC antigen expression correlates well with vulnerability of allografts to rejection. To further our studies we will employ a recently produced line of mice genetically engineered to be devoid of beta2 microglobulin expression (beta2M). Studies employing these mice which lack cell surface class I MHC antigen expression will provide us with the unique opportunity to examine the behavior of class I deficient transplants. Beta2M islet grafts will be transplanted to both xenogeneic and allogeneic recipients. Parallel in vitro studies will assess the immunogenicity of beta2M islet cells to immune mediators such as CTL, NK, and LAK cells. Utilizing spontaneously diabetic NOD mice, we will also investigate whether the absence of islet cell class I molecules alters the vulnerability of islet beta cells to autoimmune damage. In addition, by selective breeding of NOD with beta2M mice we will incorporate the defective beta2M allele into the NOD genetic background. This will allow us to determine whether expression of class I MHC antigens by beta cells is necessary for vulnerability to autoimmune insulitis and diabetes. Finally, studies will be performed using beta2M mice as recipients of islet allografts and xenografts. Since beta2M mice do not possess CD8+ class I restricted T lymphocytes the use of beta2M as recipients will allow us to determine the contribution of CD8 T cells to islet graft damage.